JP2006056832A - Method for producing and purifying 4-hydroxyquinolines - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for industrially advantageously producing high-purity 4-hydroxyquinolines from 2,3-dihydro-4(1H)-quinolines. <P>SOLUTION: The high-purity 4-hydroxyquinolines can be obtained in high yield in an industrial scale by carrying out the reaction in the presence of an alkali metal hydroxide of 0.005-5 eq. based on the 2,3-dihydro-4(1H)-quinolines, a water-soluble organic solvent and a metal catalyst by very simple operation compared to that of a conventional method when producing the 4-hydroxyquinolines represented by general formula (2) by dehydrogenating the 2,3-dihydro-4(1H)-quinolines represented by general formula (1). (In the formulas, R is an alkyl group, a benzyl group, an acyl group, an alkoxy group or a phenyl group, nonsubstituted or having a substituent; n is an integer of 0-3; and when n is 2 or 3, R may be the same or different). <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a method for producing and purifying 4-hydroxyquinolines useful as a pharmaceutical or agricultural chemical intermediate.

  As a method for producing 4-hydroxyxyquinolines represented by formula (2), which is the object of the present invention, from 2,3-dihydro-4 (1H) -quinolinones represented by formula (1), The following examples are known. A: 10% palladium carbon (hereinafter referred to as Pd / C) in an aqueous solvent, refluxed for 14 hours in the presence of 20 wt%, filtered, concentrated to dryness, washed with ether, and the remaining solid was recrystallized and purified with dioxane. Method (Non-patent Document 1). B: In an aqueous solvent, palladium black was refluxed for 8 hours in the presence of 10% by weight of palladium black, 10% by weight of Pd / C and 10% by weight of maleic acid (vs. 2,3-dihydro-4 (1H) -quinolinone). A method of making it alkaline, neutralizing with acetic acid after filtration, drying the crystals obtained by filtration, and then recrystallizing and purifying from methanol (Patent Document 1). C: A method of refluxing in the air for 6 hours in the presence of 20% by weight of 5% platinum carbon in a sodium hydroxide solution, filtering, neutralizing the filtrate with sulfuric acid, and concentrating and drying the butanol extract (Patent Document 2). D: There is a method of obtaining a target product by refluxing in the presence of 20% Pd / C in an xylene solvent for 24 hours, followed by filtration and elution with warm methanol (Non-patent Document 2). However, in these known methods, a method that requires a large amount of an expensive noble metal catalyst as a catalyst in order to obtain 4-hydroxyxyquinolines (Non-patent Document 1, Patent Document 1), filtration, neutralization, and drying after the reaction A method that requires a plurality of operations such as further recrystallization purification later, or a method that requires operations that are difficult to carry out on an industrial scale such as concentration and drying (Non-Patent Document 1, Non-Patent Document) 2 and Patent Document 2), there has been a demand for development of a production method capable of obtaining high-purity 4-hydroxyxyquinolines in an industrially advantageous manner.

J.C.S., 1950,1485-1493

USP 2,558,211

JP-A-57-171970

J. Amer. Chem. Soc., 74, 4513-4516 (1952)

An object of the present invention is to provide a process for producing high-purity 4-hydroxyquinolines from 2,3-dihydro-4 (1H) -quinolinones in an industrially advantageous manner.

（式中、Ｒは、アルキル基、ベンジル基、アシル基、アルコシキル基、フェニル基を表わし、これらは、未置換でも置換基を有していてもよい。n は０〜３の整数を表わし、nが２または３の場合、Ｒは同一であっても異なっていてもよい。）で表される２，３−ジヒドロ−４（１Ｈ）−キノリノン類を脱水素して
式（２）

（式中、Ｒ、ｎは前記の意味を表わす）
で表される４−ヒドロキシキノリン類を製造するに際し、２，３−ジヒドロ−４（１Ｈ）−キノリノン類に対して０．００５〜５当量のアルカリ金属水酸化物、水溶性有機溶媒及び金属触媒の存在下に反応することにより４−ヒドロキシキノリン類が、高純度で工業的に有利に得られることを見出し、本発明を完成するに至った。 As a result of intensive studies to solve the above problems, the present inventors have
Formula (1)

(In the formula, R represents an alkyl group, a benzyl group, an acyl group, an alkoxyl group, or a phenyl group, which may be unsubstituted or substituted. N represents an integer of 0 to 3, When n is 2 or 3, R may be the same or different.) 2,3-dihydro-4 (1H) -quinolinones represented by formula (2)

(Wherein R and n represent the above meanings)
In the production of 4-hydroxyquinolines represented by the formula: 0.005 to 5 equivalents of alkali metal hydroxide, water-soluble organic solvent and metal catalyst with respect to 2,3-dihydro-4 (1H) -quinolinones It has been found that 4-hydroxyquinolines can be obtained industrially advantageously with high purity by reacting in the presence of the present invention, and the present invention has been completed.

Hereinafter, the present invention will be described in detail.
As the metal catalyst in the present invention, for example, a noble metal such as Pd or Pt supported on a support such as activated carbon or powdered alumina, or an active metal catalyst such as Raney nickel can be used. Among these, Pd / C is preferable from the viewpoint that operability is good, metal can be recovered and economy is excellent. The metal content in the metal catalyst is usually 1 to 30%, but 5 to 20% is preferable in view of the strength of the activity and economic efficiency. The amount of catalyst used in the present invention is usually 0.01 to 0.5 times the weight of the raw material 2,3-dihydro-4 (1H) -quinolinones, but the required reaction time and operability. In view of the above, the weight is preferably 0.02 to 0.10 times.

  The water-soluble organic solvent used in the present invention can be used as long as it does not inhibit the dehydrogenation reaction, is compatible with water, and can be a recrystallization solvent for 4-hydroxyquinolines, such as acetonitrile. Nitrile solvents, ketone solvents such as acetone, ether solvents such as dioxane and ethylene glycol dimethyl ether, and alcohol solvents such as methanol, ethanol, and 2-propanol. Among these, ethanol, 2-propanol, and the like Alcohols having 1 to 3 carbon atoms are preferred. These solvents are usually used in an amount of 1 to 20 times by weight with respect to 2,3-dihydro-4 (1H) -quinolinones which are raw materials, and among these, 3 to 10 times by weight is preferable.

Examples of the alkali metal hydroxide used in the present invention include LiOH, KOH, and NaOH. The amount of alkali metal hydroxide used is 0.005 to 5 equivalents relative to 2,3-dihydro-4 (1H) -quinolinones which are raw materials, preferably 0.01 to 0.5. Equivalent, more preferably 0.05 to 0.15 equivalent.
Although the dehydrogenation reaction can be carried out in the absence of water, it is preferable to use Pd / C in a wet form of water and an alkali metal hydroxide in the form of an aqueous solution.
The reaction temperature in the present invention is usually between room temperature and the reflux temperature, and the reflux temperature is preferred from the viewpoint of the reaction rate and removal of the generated hydrogen gas out of the system.

  After completion of the dehydrogenation reaction, the alkali is neutralized with an acid, the catalyst and inorganic salts produced by the neutralization are filtered, and further concentrated to a solvent amount suitable for crystallization as necessary, followed by cooling crystallization. Highly pure 4-hydroxyquinolines can be obtained in a high yield by a very simple operation.

  By dehydrogenation by the method of the present invention, high-purity 4-hydroxyquinolines can be obtained in a high yield by an extremely simple operation compared to the conventional method on an industrial scale.

  The method of the present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples.

  In a glass reaction vessel, 2,3-dihydro-4 (1H) -quinolinone 20.0 g (136 mmol), 2-propanol 100.0 g, 29% NaOH aqueous solution 1.80 g (13 mmol) were added and dissolved. While stirring, 2.00 g of 10% Pd / C having a water content of 52.7% was added, and the mixture was stirred at a reflux temperature (about 84 ° C.) for 8 hours. When the reaction solution was analyzed by HPLC, it was 93.0% 4-hydroxyquinoline, and the raw material remaining rate was 0.4%. 1.36 g (13 mmol) of 35% hydrochloric acid was added. The Pd / C of the catalyst and the salt precipitated by the addition of hydrochloric acid were removed by filtration. After washing with 20 g of 2-propanol and distilling off 80 g of solvent under reduced pressure at a bath temperature of 77-80 ° C., cooling to an internal temperature of 10 ° C. or lower, filtering for 2 hours, filtering, and drying the resulting crystals 13.97 g of 4-hydroxyquinoline having an HPLC purity of 99.1% was obtained. Yield 70.8%

In a glass reaction vessel, 5.00 g (34.0 mmol) of 2,3-dihydro-4 (1H) -quinolinone, 25.0 g of 2-propanol, and 0.45 g (3.3 mmol) of 29% NaOH aqueous solution are dissolved. did. While stirring, 0.25 g of 10% Pd / C having a water content of 52.7% was added, and the mixture was stirred at 80 ° C. for 5 hours. 0.25 g of 10% Pd / C having a water content of 52.7% was added, and the mixture was further stirred at 80 ° C. for 4 hours. When the reaction solution was analyzed by HPLC, it was found that the area percentage was 91.8% of 4-hydroxyquinoline and the raw material 2,3-dihydro-4 (1H) -quinolinone was 0.2%.

(Comparative Example 1)
In a glass reaction vessel, 0.25 g of 2,3-dihydro-4 (1H) -quinolinone, 1.25 g of 2-propanol, and 0.25 g of water were added and dissolved. While stirring, 0.025 g of 10% Pd / C having a water content of 52.7% was added, and the mixture was stirred at 80 ° C. for 8 hours. When the reaction solution was analyzed by HPLC, the area percentage was 2.4% of 4-hydroxyquinoline and 94.1% of the raw material 2,3-dihydro-4 (1H) -quinolinone.

Claims (3)

Formula (1)

(In the formula, R represents an alkyl group, a benzyl group, an acyl group, an alkoxyl group, or a phenyl group, which may be unsubstituted or substituted. N represents an integer of 0 to 3, When n is 2 or 3, R may be the same or different.) 2,3-dihydro-4 (1H) -quinolinones represented by formula (2)

(Wherein R and n represent the above meanings)
In the production of 4-hydroxyquinolines represented by the formula: 0.005 to 5 equivalents of alkali metal hydroxide, water-soluble organic solvent and metal catalyst with respect to 2,3-dihydro-4 (1H) -quinolinones A process for producing 4-hydroxyquinolines characterized by reacting in the presence of The method for producing 4-hydroxyquinolines according to claim 1, wherein the water-soluble organic solvent contains at least one alcohol having 1 to 3 carbon atoms. Formula (2)

(Wherein R and n represent the above-mentioned meanings), in the production of 4-hydroxyquinolines, 0.005 to 5 equivalents relative to 2,3-dihydro-4 (1H) -quinolinones After the reaction in the presence of an alkali metal hydroxide, a water-soluble organic solvent and a metal catalyst, the alkali metal hydroxide is neutralized with an acid, the formed salts are removed, and further crystallization purification is performed. The purification method of 4-hydroxyquinolines of Claims 1-2.